The present invention is directed to a process for producing malto-dextrin poly(H-)sulfate and salts thereof, with the malto-dextrin poly(H-)sulfates so produced and with their utility as inhibitors of the complement system of warm-blooded animals.
Sulfation products of maltose, lactose, sucrose, manninotriose and stachyose are known, J. Pharm. Soc. Japan, 87: 1052 (1967). British J. Pharmacol., 7: 370 (1952) discloses sulfuric acid esters of starch and Acta Physiologica Scand., 8:215 (1944); 9: 28 (1945); 9 : 35 (1945); and 11 : 211 (1946), sulfuric acid esters of starch having anticoagulant and platelet agglutination activity. Certain sulfated polysaccaharides are disclosed as having anti-inflammatory action, e.g., dextran sulfate, pentosan polysulfate and amylopectin sulfate, Biochemical Pharmacology, 18:1285 (1969). Japanese Pat. No. 75/36422 (Chemical Abstracts, 83: 79544a) discloses cyclodextrin sulfates as anti-inflammatory, fatty serum clarifiers and arteriosclerotic agents. Sulfuric esters of maltose oligosaccharides have been investigated for anticoagulant activity, Chemistry and Industry, October, 1952, 982. Dextrin sulfate has been shown to possess anticoagulant acitivity, Fed. Proc., 9:188 (1950). The sulphated polysaccaharide heparin is known to have anticomplementary activity, e.g., J. Infect. Dis., 44 : 250 (1929). Pentosan polysulfo ester and dextran sulfate are also said to posses anti-complementary action, Chemical Abstracts, 52: 485h (1958) and 75:33179s (1971).
The term "complement" refers to a complex group of proteins in body fluids that, working together with antibodies or other factors, play an important role as mediators of immune, allergic, immunochemical and/or immunopathological reactions. The reactions in which complement participates takes place in blood serum or in other body fluids, and hence are considered to be humoral reactions.
With regard to human blood, there are at present more than 11 proteins in the complement system. These complement proteins are designated by the letter C and by number: C1, C2, C3 and so on up to C9. The complement protein C1 is actually an assembly of subunits designated C1q, C1r and C1s. The numbers assigned to the complement proteins reflect the sequence in which they become active, with the exception of complement protein C4, which reacts after C1 and before C2. The numerical assignments for the proteins in the complement system were made before the reaction sequence was fully understood. A more detailed discussion of the complement system and its role in body processes can be found in, for example, Bull. World Health Org., 39, 935-938 (1968); Scientific American, 229, (No. 5), 54-66 (1973); Medical World News, Oct. 11, 1974, pp. 53-58; 64-66; Harvey Lectures, 66, 75-104 (1972); The New England Journal of Medicine, 287, 489-495; 545-549; 592-596; 642-646 (1972); The Johns Hopkins Med. J., 128, 57-74 (1971); and Federation Proceedings, 32, 134-137 (1973).
The complement system can be considered to consist of three sub-systems: (1) a recognition unit (C1q) which enables it to combine with antibody molecules that have detected a foreign invader; (2) an activation unit (C1r, C1s, C2, C4, C3), which prepares a site on the neighboring membrane; and (3) an attack unit (C5, C6, C7, C8 and C9) which creates a "hole" in the membrane. The membrane attack unit is non-specific; it destroys invaders only because it is generated in their neighborhood. In order to minimize damage to the host's own cells, its activity must be limited in time. This limitation is accomplished partly by the spontaneous decay of activated complement and partly by interference by inhibitors and destructive enzymes. The control of complement, however, is not perfect, and there are times when damage is done to the host's cells. Immunity is therefore a double-edged sword.
Activation of the complement system also accelerates blood clotting. This action comes about by way of the complement-mediated release of a clotting factor from platelets. The biologically active complement fragments and complexes cn become involved in reactions that damage the host's cells, and these pathogenic reactions can result in the development of immune-complex diseases. For example, in some forms of nephritis complement damages the basal membrane of the kidney, resulting in the escape of protein from the blood into the urine. The disease disseminated lupus erythematosus belongs in this category; its symptoms include nephritis, visceral lesions and skin eruptions. The treatment of diphtheria or tetanus with the injection of large amounts of antitoxin sometimes results in serum sickness, an immune-complex disease. Rheumatoid arthritis also involves immune complexes. Like disseminated lupus erythematosus, it is an autoimmune disease, in which the disease symptoms are caused by pathological effects of the immune system in the host's tissues. In summary, the complement system has been shown to be involved with inflammation, coagulation, fibrinolysis, antibody-antigen reactions and other metabolic processes.
In the presence of antibody-antigen complexes the complement proteins are involved in a series of reactions which may lead to irreversible membrane damage if they occur in the vicinity of biological membranes. Thus, while complement constitutes a part of the body's defense mechanism against infection, it also results in inflammation and tissue damage in the immunopathological process. The nature of certain of the complement proteins, suggestions regarding the mode of complement binding to biological membranes and the manner in which complement effects membrane damage are discussed in Annual Review in Biochemistry, 38, 389 (1969).
It has been reported that the known complement inhibitors epsilon-aminocaproic acid, Suramin Sodium and tranexamic acid all have been used with success in the treatment of hereditary angioneurotic edema, a disease state resulting from an inherited deficiency or lack of function of the serum inhibitor of the activated first component of complement (C1 inhibitor), The New England Journal of Medicine, 286, 808-812 (1972); Allergol. Et. Immunopath, II, 163-168 (1974); and J. Allergy Clin. Immunol., 53, No. 5, 298-302 (1974); and Annals of Internal Medicine, 84, 580-593 (1976).